Associations of the MUC5B promoter variant with timing of interstitial lung disease and rheumatoid arthritis onset

Abstract

Objective To investigate the associations of the common MUC5B promoter variant with timing of RA-associated interstitial lung disease (RA-ILD) and RA onset. Methods We identified patients with RA meeting 2010 ACR/EULAR criteria and available genotype information in the Mass General Brigham Biobank, a multi-hospital biospecimen and clinical data collection research study. We determined RA-ILD presence by reviewing all RA patients who had computed tomography (CT) imaging, lung biopsy, or autopsy results. We determined the dates of RA and RA-ILD diagnoses by manual record review. We examined the associations of the MUC5B promoter variant (G > T at rs35705950) with RA-ILD, RA-ILD occurring before or within 2 years of RA diagnosis, and RA diagnosis at age >55 years. We used multivariable logistic regression to estimate odds ratios (OR) for each outcome by MUC5B promoter variant status, adjusting for potential confounders including genetic ancestry and smoking. Results We identified 1,005 RA patients with available genotype data for rs35705950 (mean age 45 years; 79% women; 81% European ancestry). The MUC5B promoter variant was present in 155 (15.4%) and was associated with RA-ILD (multivariable OR 3.34 [95%CI 1.97–5.60]), RA-ILD before or within 2 years of RA diagnosis (OR 4.01 [95%1.78–8.80]), and RA onset after age 55 years (OR 1.52, [95%CI 1.08–2.12]). Conclusions The common MUC5B promoter variant was associated with RA-ILD onset earlier in the RA disease course and older age of RA onset. These findings suggest that MUC5B may impact RA-ILD risk early in the RA disease course, particularly in patients with older-onset RA.

Early versus late onset interstitial lung disease in rheumatoid arthritis: An observational study of risk factors and mortality in Ontario, Canada

“…20 Recently, the MUC5B variant was also identified as a risk factor for early onset RA-ILD. 21 Wheeler et al found that MUC5B polymorphisms were less frequent in African Americans but carried a stronger association with RA-ILD. 22 In addition, environmental particulate and cigarette smoke exposure may vary by country of origin and may increase RA-ILD risk.…”

Acute and postacute COVID-19 outcomes for patients with rheumatoid arthritis: lessons learned and emerging directions 3 years into the pandemic

“…COVID-19 may be a trigger for postfibrotic lung disease in some, and RA patients are particularly susceptible to ILD [ 65 ]. This may be in part due to the MUC5B promoter variant, the strongest genetic risk factor for RA-ILD [ 66 , 67 ] that increases risk for pulmonary fibrosis after infection resolution. It is also possible that PASC could modify the RA disease course by inducing autoimmunity and promoting systemic inflammation [ 68 – 70 ].…”

Serum MUC5AC protein levels are correlated with the development and severity of connective tissue disease-associated pulmonary interstitial lesions

“…The CTD group included 70 pSS, 64 SSc, and 34 PM/DM cases. Among these CTD subgroups, ILD scores were distributed as follows: 0 (n=30), 1 (10), 2 (15), and 3 (15) in pSS; 0 (15), 1 (10), 2 (15), and 3 (24) in SSc; and 0 (7), 1 (3), 2 (11), and 3 (13) in PM/ DM. Demographic and CTD characteristics and autoantibody detection results of patients with pSS, SSc, and PM/DM are listed in Table 1, most of which were not substantially different among the distinct ILD severity scores.…”

“…The pathophysiology of CTD-ILD is unclear but genetic factors are thought to play an essential role in its development ( 8 ). Previous studies have demonstrated a strong relationship between ILDs and single nucleotide polymorphisms (SNPs) in the promoter regions of mucin 5B (MUC5B) ( 7 , 9 – 11 ) and mucin 5AC (MUC5AC) ( 12 ). MUC5AC and MUC5B, which account for approximately 90% of the mucoproteins ( 13 ), play a crucial role in the respiratory mucosal defense arsenal.…”